Scientists have demonstrated that a novel, drug-like molecule called ISRIB (integrated stress response inhibitor) can improve cognitive memory in mice.
ISRIB-treated mice display significant enhancement in spatial and fear-associated learning. The inset shows structure of ISRIB isosteromers (Jeff Miller / Carmela Sidrauski et al)
“The same biochemical pathway the molecule acts on might one day be targeted in humans to improve memory,” said Prof Peter Walter from the University of California, San Francisco, senior author of a paper published in the open-access journal eLife.
ISRIB was singled out from among 100,000 chemicals screened for their potential to perturb a protective biochemical pathway within cells that is activated when cells are unable to keep up with the need to fold proteins into their working forms. However, Prof Walter and his colleagues discovered that ISRIB acts within the cell beyond the biochemical pathway that activates this unfolded protein response, to more broadly impact what’s known as the integrated stress response. In this response, several biochemical pathways converge on a single molecular lynchpin, a protein called eIF2 alpha.
Scientists have known that in organisms ranging in complexity from yeast to humans different kinds of cellular stress trigger different enzymes to act downstream to switch off eIF2 alpha. “Among other things, the inactivation of eIF2 alpha is a brake on memory consolidation, perhaps an evolutionary consequence of a cell or organism becoming better able to adapt in other ways,” Prof Walter explained.
“Turning off eIF2 alpha dials down production of most proteins, some of which may be needed for memory formation. But eIF2 alpha inactivation also ramps up production of a few key proteins that help cells cope with stress.”
The scientists have found that ISRIB counters the effects of eIF2 alpha inactivation inside cells.
In one memory test included in the study, normal mice were able to relocate a submerged platform about three times faster after receiving injections of ISRIB than mice that received sham injections.
The mice that received the chemical also better remembered cues associated with unpleasant stimuli – the sort of fear conditioning that could help a mouse avoid being preyed upon.
“ISRIB shows good pharmacokinetic properties [how a drug is absorbed, distributed and eliminated], readily crosses the blood-brain barrier, and exhibits no overt toxicity in mice, which makes it very useful for studies in mice.”
“These properties also indicate that ISRIB might serve as a good starting point for human drug development,” Prof Walter concluded.
______
Bibliographic information: Carmela Sidrauski et al. 2013. Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife 2:e00498; doi: 10.7554/eLife.00498
